Aplastic anemia and other types of bone marrow failure have clinical and laboratory features consistent with an autoimmune pathophysiology, possibly incited by a virus. Patients with aplastic anemia show evidence of activation of cytotoxic T cells and excessive lymphokine production, especially of gamma-interferon and lymphotoxin or tumor necrosis factor. A majority of patients respond with hematologic improvement on immunosuppressive therapy. Some cases of aplastic anemia are preceded by hepatitis. Our studies have focused on aspects of the immune pathophysiology of hematopoietic suppression, the relationship of a novel hepatitis virus to this disease, as well as clinical studies. Previously we showed that one mechanism of action of gamma-interferon was induction of the Fas antigen pathway of programmed cell death. We now demonstrate that Fas expression is increased on bone marrow cells from patients with aplastic anemia in vivo, implying that this is an important process in the disease. Local effects of inhibitory molecules have been demonstrated by using recombinant DNA technology to transduce the gamma-interferon gene into human bone marrow stromal cells; endogenous production of interferon was approximately 100-fold more potent than exogenous interferon in suppression of hematopoiesis, and interferon secretion is accompanied by apoptosis as well as a block in cell cycling among CD34+ hematopoietic cells. Interferon as well as tumor necrosis factor broadly affect hematopoiesis, from primitive cells to late progenitors. The numbers of stem cells, as measured in the long term culture and initiating cell assay, is remarkably reduced in all patients with severe aplastic anemia and only modestly improved despite hematologic recovery. These results suggest irreversible loss of stem cells as a result of immune system attack. We have identified a novel flavi-pestivirus agent in the blood of several patients with the hepatitis/aplasia syndrome, as well as in other patients with aplastic anemia. The role of this virus in the etiology of aplastic anemia remains to be definitively determined. Finally, in a study of stem cell factor as treatment for refractory aplastic anemia, we have observed one clinically meaningful response in a patient who received stem cell factor followed by differentiating growth factors, granulocyte-colony stimulating factor and erythropoietin.